Multi-institutional in Belgium, Sweden, the Netherlands,
United Kingdom and Canada.

Support

Astra Draco, Sweden.

Background

The addition of long-acting inhaled beta-agonists to inhaled corticosteroids
for the treatment of moderate to severe asthma has been shown to improve
symptoms, but concerns about the development of tolerance, the masking
of symptoms of inflammation and long term effects have been raised.

This double-blind, 12-month study was designed to examine the effect
of adding a long-acting inhaled beta-agonist (formoterol) to a lower and
a higher dose of an inhaled steroid (budesonide) in patients with asthma.

Methods

Patients

Patients were enrolled at 71 centers in 9 countries, and were eligible
if they were between 18 and 70 years of age, with asthma for at least 6
months and treated with inhaled steroids for at least 3 months. FEV1
was required to be at least 50% of predicted, with at least a 15% increase
after bronchodilator treatment.

Principal exclusions: patients on high dose inhaled steroids, or who
had been on more than two courses of oral steroids (or had been hospitalized
for asthma) during the previous 6 months.

Patients who were compliant with the dose of inhaled budesonide (75%
to 125% of the prescribed dose, as assessed by a hidden dose counter) and
whose asthma was stable during the last 10 days of the run-in phase were
then randomized to one of four treatment groups.

All patients were allowed 250 mcg of inhaled terbutaline as rescue medication.

Analysis

Follow-up

Patients kept daily diaries which included twice daily, best-of-three,
peak flow measurements, asthma symptom scores, awakening due to asthma,
use of terbutaline and use of oral steroids.

There were a total of 9 clinic visits and 9 telephone follow-ups scheduled
during the study.

Endpoints

The primary endpoints were the rates of severe and mild exacerbations
of asthma per patient per year.

Severe exacerbations were those that required treatment with
oral steroids (as judged by the investigators, and which was fixed at 10
days of treatment) or that produced a decrease in peak flow of greater
than 30% from baseline for at least two consecutive days. Patients with
3 severe exacerbations within 3 months or 5 severe exacerbations total
were withdrawn from the study.

Days with mild exacerbations were defined as at least two consecutive
days with either a decrease in peak flow of 20% from baseline, an increase
in use of terbutaline of at least three per day over baseline or night
awakening due to asthma.

Results

Patients

Between April 1994 and April 1995, 1114 patients entered the run-in
phase and 852 were randomized (210-215 to each of the 4 groups).

Baseline characteristics were well-matched. There were approximately
equal numbers of men and women; average age was 42 years. FEV1
at the start of the run-in period was about 75% of predicted. At the end
of the run-in period, the average symptom score during the day was 0.5
(on a 0 to 3 scale) and the PEF was about 400 l/min.

Asthma exacerbations (primary endpoints)

Both the addition of formoterol to budesonide and increasing the dose
of budesonide independently decreased the rate of mild and severe
asthma exacerbations (i.e. there was no significant interaction between
formoterol and budesonide).

Severe exacerbations

Adding formoterol to budesonide (both low and high dose) reduced the
rate of severe exacerbations by 26%. Overall (my calculations from the
data presented) 67% of patients without formoterol were free of severe
exacerbations, vs. 76% of patients who received formoterol.

Increasing the dose of budesonide (both with and without formoterol)
reduced the rate of severe exacerbations by 49%. Overall (again, my calculations)
66% of patients on low dose budesonide were free of severe exacerbations,
vs. 76% of patients on high dose budesonide.

As noted, these effects were additive so that the high dose of budesonide
plus formoterol reduced the rate of severe exacerbations by 63%. Among
patients on both of these therapies, 80.8% were free of severe exacerbations.

Mild exacerbations

The addition of formoterol to budesonide decreased the rate of mild
exacerbations by 40%; increasing the dose of budesonide decreased the rate
by 37%.

Other indices of asthma symptoms

Other parameters of asthma symptomatology that were recorded included
mean percent of the year symptom-free, symptom score during the day and
during the night, number of inhalations of rescue medication during the
day and at night, and mean number of awakenings at night.

For all of these parameters except awakenings at night, the addition
of formoterol to budesonide significantly improved symptomatology. On the
other hand, increasing the budesonide dose from low to higher dose only
improved symptomatology for rescue medications at night and awakenings
at night.

Lung function

Parameters of lung function at the end of the study (FEV1
and peak flow) were improved by both the addition of formoterol and an
increase in budesonide dose. For peak flow, the initial improvement with
the addition of formoterol subsequently decreased, but remained statistically
significant.

Adverse events

Adverse events, withdrawals due to adverse events and hospitalizations
were similar in the four groups.

Author's discussion

The authors note that the addition of formoterol to budesonide improved
symptoms and reduced the rate of mild and severe exacerbations, without
any evidence of worsening of control after 12 months of treatment. Increasing
the dose of budesonide also reduced the rate of mild and especially of
severe exacerbations.

Although long-acting beta-agonists have been shown to improve symptomatology,
it is less clear how they would decrease the rate of severe exacerbations,
given their general lack of anti-inflammatory effect. The authors speculate
on a number of possible mechanisms, including inhibition of smooth-muscle
contraction allowing better access to steroid deposition, and a possible
anti-inflammatory effect of formoterol itself.

Concern about the development of beta-agonist tolerance and long-term
worsening of asthma control with long-acting beta-agonist inhalers does
not seem to have been borne out by this study. An initial loss of improvement
in peak flow with formoterol does imply some degree of tolerance, but this
was not clinically significant.

They note that their conclusions concerning the addition of formoterol
only apply in patients who are also receiving inhaled steroids. Also, patients
with frequent severe exacerbations appear to be better served with higher
doses of inhaled steroids than with the addition of a beta-agonist.

Comment

This study examined the effect of adding a long-acting inhaled beta-agonist
(formoterol) to two different doses of an inhaled steroid (budesonide).
The addition of formoterol significantly decreased the rate of mild and
severe exacerbations and also improved indices of symptoms. Increasing
the dose of the steroid was additive, was more effective in controlling
severe exacerbations and equally effective in controlling mild exacerbations.
Other indices of symptomatology, which were not primary endpoints, were
better controlled with formoterol than with increasing the dose of the
steroid.

Given the inflammatory nature of asthma, the use of an inhaled steroid
is considered a mainstay of therapy in patients with moderate to severe,
persistent asthma. No claim can be made based on this study for using formoterol
or any other long-acting beta-agonist without an inhaled steroid. However,
asthma is a chronic disease, many patients will be treated starting at
a young age, and inhaled steroids have at least a theoretical potential
for causing systemic side-effects. If the addition of a long-acting beta-agonist
inhaler will allow a reduction in steroid dose, this could conceivably
be advantageous in patients with mild to moderate disease who require continuous
treatment.

November 28, 1997

References

Reader Comments

Date: Wed, 3 Dec 1997
From: "Mark Leber" <besterdoc@email.msn.com>

Several questions need to be asked before we can accept the results
of this study and apply them to our patient population. First, were these
patients true asthma patients? Did they exhibit reversibility using beta
agonists? How many smoked or had other comorbid conditions such as diabetes,
hypertension, kidney disease or copd? What was the racial and ethnic character
of the experimental group? The population group may not be the same as
the patients you treat. How many patients displayed multiple allergies
or eosinophilia?

Second, I noticed that the patients only used diaries to detail their
asthma attacks. Was there a trend in using more formoterol over the course
of the study? Did any of these patients end up being seen in an emergency
department or hospitalized? The main goals of treatment should be to reduce
the long term deterioration in pulmonary function observed in asthma patients
without the steroid side effects not how to treat mild asthmatics which
I believe is fairly easy to do as demonstrated in this study.

Mark Leber,M.D.

These patients were required to have at least a 15% improvement
in FEV1 with beta-agonists. How many of them were atopic asthmatics, how
many smoked and how many had COPD was not specified and might make a difference
in the applicability of the results. I don't see how diabetes, hypertension
or kidney disease would influence the results. The ethnic make-up of the
study was not reported.

Formoterol dosage was specified a priori and was not to change during
the study. There were 11 hospitalizations for asthma: 1 in the low-dose
budesonide plus formoterol group, 2 in the high-dose budesonide plus formoterol
group, 3 in the low-dose budesonide only group and 5 in the high dose budesonide
only group. -- mj